Interaction with cyclin-dependent kinases and PCNA modulates proteasome-dependent degradation of p21
Interaction with cyclin-dependent kinases and PCNA modulates proteasome-dependent degradation of p21
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DOI：
10.1038/sj.onc.1202189
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发表时间：
1998-11-12
期刊：
影响因子：
8
通讯作者：
Ducommun, B
中科院分区：
文献类型：
--
作者：
Cayrol, C;Ducommun, B
细胞周期蛋白依赖性激酶 (CDK) 抑制剂 p21(Cip1/Waf1) 通过调节细胞周期蛋白/CDK 复合物响应各种细胞内或细胞外信号的活性，在细胞增殖控制中发挥重要作用。 p21 表达水平的微小变化可能决定它是作为细胞周期蛋白/CDK 复合物的抑制剂还是组装因子。因此，更好地表征调节 p21 丰度的机制至关重要。在这里，我们在 p53 缺陷的 DLD-1 人结肠癌细胞中使用四环素调节系统，发现 p21 蛋白水平和稳定性受蛋白酶体依赖性降解途径及其伙伴 CDK 和 PCNA 的关联调节。缺乏与 CDK 相互作用的 p21 突变体 p21(CDK-)，表现出增强的稳定性并大大降低了对蛋白酶体介导的蛋白水解的敏感性，表明与细胞周期蛋白/CDK 复合物可能引发 p21 降解。相比之下，p21突变体与PCNA相互作用受损，p21(PCNA-)表现出稳定性降低，这表明与PCNA的结合可以保护p21免受蛋白酶体依赖性降解。此外，除了蛋白质-蛋白质相互作用之外，p21 本身的丰度也可能调节 p21 的稳定性，因为我们发现高水平的 p21 表达克服了 p21 积累的蛋白酶体依赖性调节。
The cyclin-dependent kinase (CDK) inhibitor p21(Cip1/Waf1) plays an essential role in the control of cell proliferation by modulating the activity of cyclin/CDK complexes in response to various intracellular or extracellular signals. Small variations in p21 expression levels may determine whether it acts as an inhibitor or an assembly factor for cyclin/CDK complexes. It is therefore critical to better characterize the mechanisms regulating p21 abundance. Here, we show, using a tetracycline-regulated system in p53-deficient DLD-1 human colon cancer cells, that p21 protein levels and stability are regulated by the proteasome-dependent degradation pathway and by association with its partners, CDKs and PCNA, A p21 mutant deficient for interaction with CDKs, p21(CDK-), displayed an enhanced stability and greatly reduced sensitivity to proteasome-mediated proteolysis, indicating that association with cyclin/CDK complexes may trigger p21 degradation. In contrast, a p21 mutant impaired in the interaction with PCNA, p21(PCNA-), exhibited a decreased stability, suggesting that association with PCNA protects p21 from proteasome-dependent degradation. Furthermore, the abundance of p21 itself, in addition to protein-protein interactions, may also modulate p21 stability since we found that high levels of p21 expression overcome proteasome-dependent regulation of p21 accumulation.